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Hot ambient conditions and associated heat stress can increase mortality and morbidity, as well as increase adverse pregnancy outcomes and negatively affect mental health. High heat stress can also reduce physical work capacity and motor-cognitive performances, with consequences for productivity, and increase the risk of occupational health problems. Almost half of the global population and more than 1 billion workers are exposed to high heat episodes and about a third of all exposed workers have negative health effects. However, excess deaths and many heat-related health risks are preventable, with appropriate heat action plans involving behavioural strategies and biophysical solutions. Extreme heat events are becoming permanent features of summer seasons worldwide, causing many excess deaths. Heat-related morbidity and mortality are projected to increase further as climate change progresses, with greater risk associated with higher degrees of global warming. Particularly in tropical regions, increased warming might mean that physiological limits related to heat tolerance (survival) will be reached regularly and more often in coming decades. Climate change is interacting with other trends, such as population growth and ageing, urbanisation, and socioeconomic development, that can either exacerbate or ameliorate heat-related hazards. Urban temperatures are further enhanced by anthropogenic heat from vehicular transport and heat waste from buildings. Although there is some evidence of adaptation to increasing temperatures in high-income countries, projections of a hotter future suggest that without investment in research and risk management actions, heat-related morbidity and mortality are likely to increase. [ABSTRACT FROM AUTHOR]

Background: About a third of women receiving pethidine for labour pain subsequently require an epidural, which provides effective pain relief but increases the risk of instrumental vaginal delivery. Remifentanil patient-controlled analgesia (PCA) in labour is an alternative to pethidine, but is not widely used. We aimed to evaluate epidural analgesia progression among women using remifentanil PCA compared with pethidine.Methods: We did an open-label, multicentre, randomised controlled trial in 14 UK maternity units. We included women aged 16 years or older, beyond 37 weeks' gestation, in labour with a singleton cephalic presentation, and who requested opioid pain relief. We randomly assigned eligible participants (1:1) to either the intravenous remifentanil PCA group (40 μg bolus on demand with a 2 min lockout) or the intramuscular pethidine group (100 mg every 4 h, up to 400 mg in 24 h), using a web-based or telephone randomisation service with a minimisation algorithm for parity, maternal age, ethnicity, and mode of labour onset. Because of the differences in routes of drug administration, study participants and health-care providers were not masked to the group allocation. The primary outcome was the proportion of women who received epidural analgesia after enrolment for pain relief in labour. Primary analyses were unadjusted and analysed by the intention-to-treat principle. This study is registered with the ISRCTN registry, number ISRCTN29654603.Findings: Between May 13, 2014, and Sept 2, 2016, 201 women were randomly assigned to the remifentanil PCA group and 200 to the pethidine group. One participant in the pethidine group withdrew consent, leaving 199 for analyses. The proportions of epidural conversion were 19% (39 of 201) in the remifentanil PCA group and 41% (81 of 199) in the pethidine group (risk ratio 0·48, 95% CI 0·34-0·66; p<0·0001). There were no serious adverse events or drug reactions directly attributable to either analgesic during the study.Interpretation: Intravenous remifentanil PCA halved the proportion of epidural conversions compared with intramuscular pethidine. This finding challenges routine pethidine use as standard of care in labour.Funding: National Institute for Health Research Clinician Scientist Award. [ABSTRACT FROM AUTHOR]

Background: Treatment-resistant major depressive disorder is common; repetitive transcranial magnetic stimulation (rTMS) by use of high-frequency (10 Hz) left-side dorsolateral prefrontal cortex stimulation is an evidence-based treatment for this disorder. Intermittent theta burst stimulation (iTBS) is a newer form of rTMS that can be delivered in 3 min, versus 37·5 min for a standard 10 Hz treatment session. We aimed to establish the clinical effectiveness, safety, and tolerability of iTBS compared with standard 10 Hz rTMS in adults with treatment-resistant depression.Methods: In this randomised, multicentre, non-inferiority clinical trial, we recruited patients who were referred to specialty neurostimulation centres based at three Canadian university hospitals (Centre for Addiction and Mental Health and Toronto Western Hospital, Toronto, ON, and University of British Columbia Hospital, Vancouver, BC). Participants were aged 18-65 years, were diagnosed with a current treatment-resistant major depressive episode or could not tolerate at least two antidepressants in the current episode, were receiving stable antidepressant medication doses for at least 4 weeks before baseline, and had an HRSD-17 score of at least 18. Participants were randomly allocated (1:1) to treatment groups (10 Hz rTMS or iTBS) by use of a random permuted block method, with stratification by site and number of adequate trials in which the antidepressants were unsuccessful. Treatment was delivered open-label but investigators and outcome assessors were masked to treatment groups. Participants were treated with 10 Hz rTMS or iTBS to the left dorsolateral prefrontal cortex, administered on 5 days a week for 4-6 weeks. The primary outcome measure was change in 17-item Hamilton Rating Scale for Depression (HRSD-17) score, with a non-inferiority margin of 2·25 points. For the primary outcome measure, we did a per-protocol analysis of all participants who were randomly allocated to groups and who attained the primary completion point of 4 weeks. This trial is registered with ClinicalTrials.gov, number NCT01887782.Findings: Between Sept 3, 2013, and Oct 3, 2016, we randomly allocated 205 participants to receive 10 Hz rTMS and 209 participants to receive iTBS. 192 (94%) participants in the 10 Hz rTMS group and 193 (92%) in the iTBS group were assessed for the primary outcome after 4-6 weeks of treatment. HRSD-17 scores improved from 23·5 (SD 4·4) to 13·4 (7·8) in the 10 Hz rTMS group and from 23·6 (4·3) to 13·4 (7·9) in the iTBS group (adjusted difference 0·103 [corrected], lower 95% CI -1·16; p=0·0011), which indicated non-inferiority of iTBS. Self-rated intensity of pain associated with treatment was greater in the iTBS group than in the 10 Hz rTMS group (mean score on verbal analogue scale 3·8 [SD 2·0] vs 3·4 [2·0] out of 10; p=0·011). Dropout rates did not differ between groups (10 Hz rTMS: 13 [6%] of 205 participants; iTBS: 16 [8%] of 209 participants); p=0·6004). The most common treatment-related adverse event was headache in both groups (10 Hz rTMS: 131 [64%] of 204; iTBS: 136 [65%] of 208).Interpretation: In patients with treatment-resistant depression, iTBS was non-inferior to 10 Hz rTMS for the treatment of depression. Both treatments had low numbers of dropouts and similar side-effects, safety, and tolerability profiles. By use of iTBS, the number of patients treated per day with current rTMS devices can be increased several times without compromising clinical effectiveness.Funding: Canadian Institutes of Health Research. [ABSTRACT FROM AUTHOR]

Background: There is a need to increase access to surgical treatments in African countries, but perioperative complications represent a major global health-care burden. There are few studies describing surgical outcomes in Africa.Methods: We did a 7-day, international, prospective, observational cohort study of patients aged 18 years and older undergoing any inpatient surgery in 25 countries in Africa (the African Surgical Outcomes Study). We aimed to recruit as many hospitals as possible using a convenience sampling survey, and required data from at least ten hospitals per country (or half the surgical centres if there were fewer than ten hospitals) and data for at least 90% of eligible patients from each site. Each country selected one recruitment week between February and May, 2016. The primary outcome was in-hospital postoperative complications, assessed according to predefined criteria and graded as mild, moderate, or severe. Data were presented as median (IQR), mean (SD), or n (%), and compared using t tests. This study is registered on the South African National Health Research Database (KZ_2015RP7_22) and ClinicalTrials.gov (NCT03044899).Findings: We recruited 11 422 patients (median 29 [IQR 10-70]) from 247 hospitals during the national cohort weeks. Hospitals served a median population of 810 000 people (IQR 200 000-2 000 000), with a combined number of specialist surgeons, obstetricians, and anaesthetists totalling 0·7 (0·2-1·9) per 100 000 population. Hospitals did a median of 212 (IQR 65-578) surgical procedures per 100 000 population each year. Patients were younger (mean age 38·5 years [SD 16·1]), with a lower risk profile (American Society of Anesthesiologists median score 1 [IQR 1-2]) than reported in high-income countries. 1253 (11%) patients were infected with HIV, 6504 procedures (57%) were urgent or emergent, and the most common procedure was caesarean delivery (3792 patients, 33%). Postoperative complications occurred in 1977 (18·2%, 95% CI 17·4-18·9]) of 10 885 patients. 239 (2·1%) of 11 193 patients died, 225 (94·1%) after the day of surgery. Infection was the most common complication (1156 [10·2%] of 10 970 patients), of whom 112 (9·7%) died.Interpretation: Despite a low-risk profile and few postoperative complications, patients in Africa were twice as likely to die after surgery when compared with the global average for postoperative deaths. Initiatives to increase access to surgical treatments in Africa therefore should be coupled with improved surveillance for deteriorating physiology in patients who develop postoperative complications, and the resources necessary to achieve this objective.Funding: Medical Research Council of South Africa. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder.Methods: We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291.Findings: We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89-2·41) for amitriptyline and 1·37 (1·16-1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72-0·97) and fluoxetine (0·88, 0·80-0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01-1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19-1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51-0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43-0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30-2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low.Interpretation: All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants.Funding: National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science. [ABSTRACT FROM AUTHOR]

Background: Canakinumab, a monoclonal antibody targeting interleukin-1β, reduces inflammation and cardiovascular event rates with no effect on lipid concentrations. However, it is uncertain which patient groups benefit the most from treatment and whether reductions in the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) correlate with clinical benefits for individual patients.Methods: The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) used computer-generated codes to randomly allocate 10 061 men and women with a history of myocardial infarction to placebo or one of three doses of canakinumab (50 mg, 150 mg, or 300 mg) given subcutaneously once every 3 months. In a prespecified secondary analysis designed to address the relationship of hsCRP reduction to event reduction in CANTOS, we evaluated the effects of canakinumab on rates of major adverse cardiovascular events, cardiovascular mortality, and all-cause mortality according to on-treatment concentrations of hsCRP. We used multivariable modelling to adjust for baseline factors associated with achieved hsCRP and multiple sensitivity analyses to address the magnitude of residual confounding. The median follow-up was 3·7 years. The trial is registered with ClinicalTrials.gov, number NCT01327846.Findings: Baseline clinical characteristics did not define patient groups with greater or lesser cardiovascular benefits when treated with canakinumab. However, trial participants allocated to canakinumab who achieved hsCRP concentrations less than 2 mg/L had a 25% reduction in major adverse cardiovascular events (multivariable adjusted hazard ratio [HRadj]=0·75, 95% CI 0·66-0·85, p<0·0001), whereas no significant benefit was observed among those with on-treatment hsCRP concentrations of 2 mg/L or above (HRadj=0·90, 0·79-1·02, p=0·11). For those treated with canakinumab who achieved on-treatment hsCRP concentrations less than 2 mg/L, cardiovascular mortality (HRadj=0·69, 95% CI 0·56-0·85, p=0·0004) and all-cause mortality (HRadj=0·69, 0·58-0·81, p<0·0001) were both reduced by 31%, whereas no significant reduction in these endpoints was observed among those treated with canakinumab who achieved hsCRP concentrations of 2 mg/L or above. Similar differential effects were found in analyses of the trial prespecified secondary cardiovascular endpoint (which additionally included hospitalisation for unstable angina requiring unplanned revascularisation) and in sensitivity analyses alternatively based on median reductions in hsCRP, on 50% or greater reductions in hsCRP, on the median percent reduction in hsCRP, in dose-specific analyses, and in analyses using a causal inference approach to estimate the effect of treatment among individuals who would achieve a targeted hsCRP concentration.Interpretation: The magnitude of hsCRP reduction following a single dose of canakinumab might provide a simple clinical method to identify individuals most likely to accrue the largest benefit from continued treatment. These data further suggest that lower is better for inflammation reduction with canakinumab.Funding: Novartis Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Background: Physical activity has a protective effect against cardiovascular disease (CVD) in high-income countries, where physical activity is mainly recreational, but it is not known if this is also observed in lower-income countries, where physical activity is mainly non-recreational. We examined whether different amounts and types of physical activity are associated with lower mortality and CVD in countries at different economic levels.Methods: In this prospective cohort study, we recruited participants from 17 countries (Canada, Sweden, United Arab Emirates, Argentina, Brazil, Chile, Poland, Turkey, Malaysia, South Africa, China, Colombia, Iran, Bangladesh, India, Pakistan, and Zimbabwe). Within each country, urban and rural areas in and around selected cities and towns were identified to reflect the geographical diversity. Within these communities, we invited individuals aged between 35 and 70 years who intended to live at their current address for at least another 4 years. Total physical activity was assessed using the International Physical Activity Questionnaire (IPQA). Participants with pre-existing CVD were excluded from the analyses. Mortality and CVD were recorded during a mean of 6·9 years of follow-up. Primary clinical outcomes during follow-up were mortality plus major CVD (CVD mortality, incident myocardial infarction, stroke, or heart failure), either as a composite or separately. The effects of physical activity on mortality and CVD were adjusted for sociodemographic factors and other risk factors taking into account household, community, and country clustering.Findings: Between Jan 1, 2003, and Dec 31, 2010, 168 916 participants were enrolled, of whom 141 945 completed the IPAQ. Analyses were limited to the 130 843 participants without pre-existing CVD. Compared with low physical activity (<600 metabolic equivalents [MET] × minutes per week or <150 minutes per week of moderate intensity physical activity), moderate (600-3000 MET × minutes or 150-750 minutes per week) and high physical activity (>3000 MET × minutes or >750 minutes per week) were associated with graded reduction in mortality (hazard ratio 0·80, 95% CI 0·74-0·87 and 0·65, 0·60-0·71; p<0·0001 for trend), and major CVD (0·86, 0·78-0·93; p<0·001 for trend). Higher physical activity was associated with lower risk of CVD and mortality in high-income, middle-income, and low-income countries. The adjusted population attributable fraction for not meeting the physical activity guidelines was 8·0% for mortality and 4·6% for major CVD, and for not meeting high physical activity was 13·0% for mortality and 9·5% for major CVD. Both recreational and non-recreational physical activity were associated with benefits.Interpretation: Higher recreational and non-recreational physical activity was associated with a lower risk of mortality and CVD events in individuals from low-income, middle-income, and high-income countries. Increasing physical activity is a simple, widely applicable, low cost global strategy that could reduce deaths and CVD in middle age.Funding: Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, Ontario SPOR Support Unit, Ontario Ministry of Health and Long-Term Care, AstraZeneca, Sanofi-Aventis, Boehringer Ingelheim, Servier, GSK, Novartis, King Pharma, and national and local organisations in participating countries that are listed at the end of the Article. [ABSTRACT FROM AUTHOR]

Background: Carotid baroreflex activation lowers blood pressure and might have potential application for the treatment of resistant hypertension. We did a proof-of-principle trial with a novel endovascular baroreceptor amplification device, MobiusHD (Vascular Dynamics, Mountain View, CA, USA), in patients with resistant hypertension.Methods: CALM-FIM_EUR was a prospective, first-in-human, open-label study done at six European centres. Eligible patients were adults with resistant hypertension (office systolic blood pressure ≥160 mm Hg despite taking at least three antihypertensive agents, including a diuretic). MobiusHD devices were implanted unilaterally in the internal carotid artery. The primary endpoint was the incidence of serious adverse events at 6 months. Secondary endpoints included changes in office and 24 h ambulatory blood pressure. This trial is registered with ClinicalTrials.gov, number NCT01911897.Findings: Between December, 2013, and February, 2016, 30 patients were enrolled and underwent successful implantation. Mean age was 52 years (SD 12), 15 patients (50%) were men, and mean antihypertensive use was 4·4 drugs (1·4). Mean office blood pressure was 184/109 mm Hg (18/14) at baseline and was reduced by 24/12 mm Hg (13-34/6-18) at 6 months (p=0·0003 for systolic and p=0·0001 diastolic blood pressure). Mean baseline 24 h ambulatory blood pressure was 166/100 mm Hg (17/14) at baseline and was reduced by 21/12 mm Hg (14-29/7-16) at 6 months (p<0·0001 for systolic and diastolic blood pressure). Five serious adverse events had occurred in four patients (13%) at 6 months: hypotension (n=2), worsening hypertension (n=1), intermittent claudication (n=1) and wound infection (n=1).Interpretation: In patients with resistant hypertension, endovascular baroreceptor amplification with the MobiusHD device substantially lowered blood pressure with an acceptable safety profile. Randomised, double-blind, sham-controlled trials are warranted to investigate the use of this treatment further.Funding: Vascular Dynamics. [ABSTRACT FROM AUTHOR]

Introduction: Ritual circumcision complicated by gangrene is a leading cause of penile loss in young men in South Africa. This deeply rooted cultural tradition is unlikely to be abolished. Conventional reconstructive techniques using free vascularised tissue flaps with penile implants are undesirable in this often socioeconomically challenged group because donor site morbidity can hinder manual labour and vigorous sexual activity might lead to penile implant extrusion. The psychosociological effects of penile loss in a young man are devastating and replacing it with the same organ is likely to produce the maximum benefit.Methods: We first performed a cadaver-to-cadaver penile transplantation as preparation. After approval from the Human Research Ethics Committee was obtained, we recruited potential recipients. We screened the potential participants for both physical and psychological characteristics, including penile stump length, and emotional suitability for the procedure. A suitable donor became available and the penis was harvested. We surgically prepared the penile stump of the recipient and attached the penile graft. Immunosuppression treatment with antithymyocyte globulin, methylprednisolone, tacrolimus, mycophenolate mofetil, and prednisone were commenced. Tadalafil at 5 mg once per day was commenced after 1 week as penile rehabilitation and was continued for 3 months. We collected on quality-of-life scores (Short Form 36 version 2 [SF-36v2] questionnaires) before surgery and during follow-up and measured erectile function (International Index for Erectile Function [IIEF] score) and urine flow rates at 24 months post transplant.Findings: The warm ischaemia time for the graft after removal was 4 min and the cold ischaemia time was 16 h. The surgery lasted 9 h. An arterial thrombus required urgent revision 8 h after the operation. On post operative day 6, an infected haematoma and an area of proximal skin necrosis were surgically treated. The recipient was discharged after 1 month and first reported satisfactory sexual intercourse 1 week later (despite advice to the contrary). The recipient reported regular sexual intercourse from 3 months after the operation. An episode of acute kidney injury at 7 months was reversed by reducing the tacrolimus dose to 14 mg twice per day. At 8 months after surgery, the patient had a skin infection with phaeohyphomycosis due to Alternaria alternata, which we treated with topical antifungal medication. Quality-of-life scores improved substantially after the operation (SF-36v2 mental health scores improved from 25 preoperatively, to 57 at 6 months and 46 at 24 months post transplant; physical health scores improved from 37 at baseline to 60 at 6 months and 59 at 24 months post-transplant). At 24 months, measured maximum urine flow rate (16·3 mL/s from a volume voided of 109 mL) and IIEF score (overall satisfaction score of 8 from a maximum of 10) were normal, showing normal voiding and erectile function, respectively.Interpretation: Penile transplantation restored normal physiological functions in this transplant recipient without major complications in the first 24 months.Funding: Department of Health, Western Cape Government. [ABSTRACT FROM AUTHOR]

Anxiety disorders (separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder, panic disorder, agoraphobia, and generalised anxiety disorder) are common and disabling conditions that mostly begin during childhood, adolescence, and early adulthood. They differ from developmentally normative or stress-induced transient anxiety by being marked (ie, out of proportion to the actual threat present) and persistent, and by impairing daily functioning. Most anxiety disorders affect almost twice as many women as men. They often co-occur with major depression, alcohol and other substance-use disorders, and personality disorders. Differential diagnosis from physical conditions-including thyroid, cardiac, and respiratory disorders, and substance intoxication and withdrawal-is imperative. If untreated, anxiety disorders tend to recur chronically. Psychological treatments, particularly cognitive behavioural therapy, and pharmacological treatments, particularly selective serotonin-reuptake inhibitors and serotonin-noradrenaline-reuptake inhibitors, are effective, and their combination could be more effective than is treatment with either individually. More research is needed to increase access to and to develop personalised treatments. [ABSTRACT FROM AUTHOR]

Background: Impaired contractility is a feature of heart failure with reduced ejection fraction. We assessed the pharmacokinetics and effects on cardiac function and structure of the cardiac myosin activator, omecamtiv mecarbil.Methods: In this randomised, double-blind study, done at 87 sites in 13 countries, we recruited patients with stable, symptomatic chronic heart failure and left ventricular ejection fraction 40% or lower. Patients were randomly assigned equally, via an interactive web response system, to receive 25 mg oral omecamtiv mecarbil twice daily (fixed-dose group), 25 mg twice daily titrated to 50 mg twice daily guided by pharmacokinetics (pharmacokinetic-titration group), or placebo for 20 weeks. We assessed the maximum concentration of omecamtiv mecarbil in plasma (primary endpoint) and changes in cardiac function and ventricular diameters. This trial is registered with ClinicalTrials.gov, number NCT01786512.Findings: From March 17, 2014, to March 5, 2015, we enrolled 150 patients in the fixed-dose omecamtiv mecarbil group and 149 in the pharmacokinetic-titration and placebo groups. Mean maximum concentration of omecamtiv mecarbil at 12 weeks was 200 (SD 71) ng/mL in the fixed-dose group and 318 (129) ng/mL in the pharmacokinetic-titration group. For the pharmacokinetic-titration group versus placebo group at 20 weeks, least square mean differences were as follows: systolic ejection time 25 ms (95% CI 18-32, p<0·0001), stroke volume 3·6 mL (0·5-6·7, p=0·0217), left ventricular end-systolic diameter -1·8 mm (-2·9 to -0·6, p=0·0027), left ventricular end-diastolic diameter -1·3 mm, (-2·3 to 0·3, p=0·0128), heart rate -3·0 beats per min (-5·1 to -0·8, p=0·0070), and N-terminal pro B-type natriuretic peptide concentration in plasma -970 pg/mL (-1672 to -268, p=0·0069). The frequency of adverse clinical events did not differ between groups.Interpretation: Omecamtiv mecarbil dosing guided by pharmacokinetics achieved plasma concentrations associated with improved cardiac function and decreased ventricular diameter.Funding: Amgen. [ABSTRACT FROM AUTHOR]

Background: CTX0E03 is an immortalised human neural stem-cell line from which a drug product (CTX-DP) was developed for allogeneic therapy. Dose-dependent improvement in sensorimotor function in rats implanted with CTX-DP 4 weeks after middle cerebral artery occlusion stroke prompted investigation of the safety and tolerability of this treatment in stroke patients.Methods: We did an open-label, single-site, dose-escalation study. Men aged 60 years or older with stable disability (National Institutes of Health Stroke Scale [NIHSS] score ≥6 and modified Rankin Scale score 2-4) 6-60 months after ischaemic stroke were implanted with single doses of 2 million, 5 million, 10 million, or 20 million cells by stereotactic ipsilateral putamen injection. Clinical and brain imaging data were collected over 2 years. The primary endpoint was safety (adverse events and neurological change). This trial is registered with ClinicalTrials.gov, number NCT01151124.Findings: 13 men were recruited between September, 2010, and January, 2013, of whom 11 (mean age 69 years, range 60-82) received CTX-DP. Median NIHSS score before implantation was 7 (IQR 6-8) and the mean time from stroke was 29 (SD 14) months. Three men had subcortical infarcts only and seven had right-hemisphere infarcts. No immunological or cell-related adverse events were seen. Other adverse events were related to the procedure or comorbidities. Hyperintensity around the injection tracts on T2-weighted fluid-attenuation inversion recovery MRI was seen in five patients. At 2 years, improvement in NIHSS score ranged from 0 to 5 (median 2) points.Interpretation: Single intracerebral doses of CTX-DP up to 20 million cells induced no adverse events and were associated with improved neurological function. Our observations support further investigation of CTX-DP in stroke patients.Funding: ReNeuron Limited. [ABSTRACT FROM AUTHOR]

Sickle-cell disease affects millions of individuals worldwide, but the global incidence is concentrated in Africa. The burden of sickle-cell disease is expected to continue to rise over the coming decades, adding to stress on the health infrastructures of many countries. Although the molecular cause of sickle-cell disease has been known for more than half a century, treatment options remain greatly limited. Allogeneic haemopoietic stem-cell transplantation is the only existing cure but is limited to specialised clinical centres and remains inaccessible for most patients. Induction of fetal haemoglobin production is a promising strategy for the treatment of sickle-cell disease. In this Series paper, we review scientific breakthroughs in epidemiology, genetics, and molecular biology that have brought reactivation of fetal haemoglobin to the forefront of sickle-cell disease research. Improved knowledge of the regulation of fetal haemoglobin production in human beings and the development of genome editing technology now support the design of innovative therapies for sickle-cell disease that are based on fetal haemoglobin. [ABSTRACT FROM AUTHOR]

The article offers information on the Lancet Commission, the commission of the journal intended for the health and wellbeing of adolescents around the globe. Topics discussed include the global forces for adolescent health, the sustainability of ecosystems, better childhood nutrition and health, and the investments for international development community.

Background: New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma.Methods: In this open-label, multicentre, phase 2 trial done in Canada, Spain, and the USA, patients (age ≥18 years) with multiple myeloma who were previously treated with at least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to decide the dose for further assessment in part 2. Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3-6), and then every 4 weeks thereafter (cycle 7 and higher). The allocation schedule was computer-generated and randomisation, with permuted blocks, was done centrally with an interactive web response system. In part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 1. The primary endpoint was overall response rate (partial response [PR] + very good PR + complete response [CR] + stringent CR). All patients who received at least one dose of daratumumab were included in the analysis. The trial is registered with ClinicalTrials.gov, number NCT01985126.Findings: The study is ongoing. In part 1 stage 1 of the study, 18 patients were randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 and 2. Patients received a median of five previous lines of therapy (range 2-14). 85 (80%) patients had previously received autologous stem cell transplantation, 101 (95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29.2%, 95% CI 20.8-38.9)-three (2.8%, 0.6-8.0) had a stringent CR, ten (9.4%, 4.6-16.7) had a very good PR, and 18 (17.0%, 10.4-25.5) had a PR. The median time to first response was 1.0 month (range 0.9-5.6). Median duration of response was 7.4 months (95% CI 5.5-not estimable) and progression-free survival was 3.7 months (95% CI 2.8-4.6). The 12-month overall survival was 64.8% (95% CI 51.2-75.5) and, at a subsequent cutoff, median overall survival was 17.5 months (95% CI 13.7-not estimable). Daratumumab was well tolerated; fatigue (42 [40%] patients) and anaemia (35 [33%]) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation.Interpretation: Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients.Funding: Janssen Research & Development. [ABSTRACT FROM AUTHOR]

Background: Isavuconazole is a novel triazole with broad-spectrum antifungal activity. The SECURE trial assessed efficacy and safety of isavuconazole versus voriconazole in patients with invasive mould disease.Methods: This was a phase 3, double-blind, global multicentre, comparative-group study. Patients with suspected invasive mould disease were randomised in a 1:1 ratio using an interactive voice-web response system, stratified by geographical region, allogeneic haemopoietic stem cell transplantation, and active malignant disease at baseline, to receive isavuconazonium sulfate 372 mg (prodrug; equivalent to 200 mg isavuconazole; intravenously three times a day on days 1 and 2, then either intravenously or orally once daily) or voriconazole (6 mg/kg intravenously twice daily on day 1, 4 mg/kg intravenously twice daily on day 2, then intravenously 4 mg/kg twice daily or orally 200 mg twice daily from day 3 onwards). We tested non-inferiority of the primary efficacy endpoint of all-cause mortality from first dose of study drug to day 42 in patients who received at least one dose of the study drug (intention-to-treat [ITT] population) using a 10% non-inferiority margin. Safety was assessed in patients who received the first dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00412893.Findings: 527 adult patients were randomly assigned (258 received study medication per group) between March 7, 2007, and March 28, 2013. All-cause mortality from first dose of study drug to day 42 for the ITT population was 19% with isavuconazole (48 patients) and 20% with voriconazole (52 patients), with an adjusted treatment difference of -1·0% (95% CI -7·8 to 5·7). Because the upper bound of the 95% CI (5·7%) did not exceed 10%, non-inferiority was shown. Most patients (247 [96%] receiving isavuconazole and 255 [98%] receiving voriconazole) had treatment-emergent adverse events (p=0·122); the most common were gastrointestinal disorders (174 [68%] vs 180 [69%]) and infections and infestations (152 [59%] vs 158 [61%]). Proportions of patients with treatment-emergent adverse events by system organ class were similar overall. However, isavuconazole-treated patients had a lower frequency of hepatobiliary disorders (23 [9%] vs 42 [16%]; p=0·016), eye disorders (39 [15%] vs 69 [27%]; p=0·002), and skin or subcutaneous tissue disorders (86 [33%] vs 110 [42%]; p=0·037). Drug-related adverse events were reported in 109 (42%) patients receiving isavuconazole and 155 (60%) receiving voriconazole (p<0·001).Interpretation: Isavuconazole was non-inferior to voriconazole for the primary treatment of suspected invasive mould disease. Isavuconazole was well tolerated compared with voriconazole, with fewer study-drug-related adverse events. Our results support the use of isavuconazole for the primary treatment of patients with invasive mould disease.Funding: Astellas Pharma Global Development, Basilea Pharmaceutica International. [ABSTRACT FROM AUTHOR]

Background: Percutaneous tibial nerve stimulation (PTNS) is a new ambulatory therapy for faecal incontinence. Data from case series suggest it has beneficial outcomes in 50-80% patients; however its effectiveness against sham electrical stimulation has not been investigated. We therefore aimed to assess the short-term efficacy of PTNS against sham electrical stimulation in adults with faecal incontinence.Methods: We did a double-blind, multicentre, pragmatic, parallel-group, randomised controlled trial (CONtrol of Faecal Incontinence using Distal NeuromodulaTion [CONFIDeNT]) in 17 specialist hospital units in the UK that had the skills to manage patients with faecal incontinence. Eligible participants aged 18 years or older with substantial faecal incontinence for whom conservative treatments (such as dietary changes and pelvic floor exercises) had not worked, were randomly assigned (1:1) to receive either PTNS (via the Urgent PC neuromodulation system) or sham stimulation (via a transcutaneous electrical nerve stimulation machine to the lateral forefoot) once per week for 12 weeks. Randomisation was done with permuted block sizes of two, four, and six, and was stratified by sex and then by centre for women. Patients and outcome assessors were both masked to treatment allocation for the 14-week duration of the trial (but investigators giving the treatment were not masked). The primary outcome was a clinical response to treatment, which we defined as a 50% or greater reduction in episodes of faecal incontinence per week. We assessed this outcome after 12 treatment sessions, using data from patients' bowel diaries. Analysis was by intention to treat, and missing data were multiply imputed. This trial is registered with the ISRCTN registry, number 88559475, and is closed to new participants.Findings: Between Jan 23, 2012, and Oct 31, 2013, we randomly assigned 227 eligible patients (of 373 screened) to receive either PTNS (n=115) or sham stimulation (n=112). 12 patients withdrew from the trial: seven from the PTNS group and five from the sham group (mainly because they could not commit to receiving treatment every week). Two patients (one in each group) withdrew because of an adverse event that was unrelated to treatment (exacerbation of fibromyalgia and rectal bleeding). 39 (38%) of 103 patients with full data from bowel diaries in the PTNS group had a 50% or greater reduction in the number of episodes of faecal incontinence per week compared with 32 (31%) of 102 patients in the sham group (adjusted odds ratio 1·28, 95% CI 0·72-2·28; p=0·396). No serious adverse events related to treatment were reported in the trial. Seven mild, related adverse events were reported in each treatment group, mainly pain at the needle site (four in PTNS, three in sham).Interpretation: PTNS given for 12 weeks did not confer significant clinical benefit over sham electrical stimulation in the treatment of adults with faecal incontinence. Further studies are warranted to determine its efficacy in the long term, and in patient subgroups (ie, those with urgency).Funding: National Institute for Health Research. [ABSTRACT FROM AUTHOR]

Epithelial ovarian cancer is the commonest cause of gynaecological cancer-associated death. The disease typically presents in postmenopausal women, with a few months of abdominal pain and distension. Most women have advanced disease (International Federation of Gynecology and Obstetrics [FIGO] stage III), for which the standard of care remains surgery and platinum-based cytotoxic chemotherapy. Although this treatment can be curative for most patients with early stage disease, most women with advanced disease will develop many episodes of recurrent disease with progressively shorter disease-free intervals. These episodes culminate in chemoresistance and ultimately bowel obstruction, the most frequent cause of death. For women whose disease continues to respond to platinum-based drugs, the disease can often be controlled for 5 years or more. Targeted treatments such as antiangiogenic drugs or poly (ADP-ribose) polymerase inhibitors offer potential for improved survival. The efficacy of screening, designed to detect the disease at an earlier and curable stage remains unproven, with key results expected in 2015. [ABSTRACT FROM AUTHOR]

The article discusses discovery of new pathways in treatment of menopausal hot flushes. Topics include characteristics of hot flushes, or vasomotor symptoms, which are experienced by a significant percentage of postmenopausal women, and cause sleep disturbances, fatigue, and decreased cognitive function; oestrogen deficiency; and placebo-controlled trial studying the oral neurokinin 3 receptor (NK3R) antagonist MLE4901 as a new therapy for menopausal hot flushes, published in the journal.

The article discusses the effort made by doctors and pain specialists to improve the medical care and services provided to patients who suffer from chronic pain. The article further discusses the need for chronic pain to be recognised as a disease which may help in the enhancement of treatment availability.

The article discusses the need to improve the contractile performance of failing hearts by developing a safe therapeutic agent. The article also discusses that agents that have beneficial haemodynamic effects have been known to improve contractility, however, their continued use may result in a rise in the risk of mortality and morbidity.

The authors discuss the commitments of the member states of the World Health Organization (WHO) to reduce the prevalence of insufficient physical activity and non-communicable diseases (NCDs) in Thailand. Topics mentioned include the mortality, as well as health spending, in the country due to NCDs, the challenges associated with increasing physical activity and to reduce mortality risk related to the disease, and the Thailand Healthy Lifestyle Strategic Plan 2011-2020.

Adrenal insufficiency is the clinical manifestation of deficient production or action of glucocorticoids, with or without deficiency also in mineralocorticoids and adrenal androgens. It is a life-threatening disorder that can result from primary adrenal failure or secondary adrenal disease due to impairment of the hypothalamic-pituitary axis. Prompt diagnosis and management are essential. The clinical manifestations of primary adrenal insufficiency result from deficiency of all adrenocortical hormones, but they can also include signs of other concurrent autoimmune conditions. In secondary or tertiary adrenal insufficiency, the clinical picture results from glucocorticoid deficiency only, but manifestations of the primary pathological disorder can also be present. The diagnostic investigation, although well established, can be challenging, especially in patients with secondary or tertiary adrenal insufficiency. We summarise knowledge at this time on the epidemiology, causal mechanisms, pathophysiology, clinical manifestations, diagnosis, and management of this disorder. INSET: Panel: Prevention and therapeutic management of adrenal.... [ABSTRACT FROM AUTHOR]

Glucose metabolism is normally regulated by a feedback loop including islet β cells and insulin-sensitive tissues, in which tissue sensitivity to insulin affects magnitude of β-cell response. If insulin resistance is present, β cells maintain normal glucose tolerance by increasing insulin output. Only when β cells cannot release sufficient insulin in the presence of insulin resistance do glucose concentrations rise. Although β-cell dysfunction has a clear genetic component, environmental changes play an essential part. Modern research approaches have helped to establish the important role that hexoses, aminoacids, and fatty acids have in insulin resistance and β-cell dysfunction, and the potential role of changes in the microbiome. Several new approaches for treatment have been developed, but more effective therapies to slow progressive loss of β-cell function are needed. Recent findings from clinical trials provide important information about methods to prevent and treat type 2 diabetes and some of the adverse effects of these interventions. However, additional long-term studies of drugs and bariatric surgery are needed to identify new ways to prevent and treat type 2 diabetes and thereby reduce the harmful effects of this disease. [ABSTRACT FROM AUTHOR]

Background Pelvic organ prolapse is common and is strongly associated with childbirth and increasing age. Women with prolapse are often advised to do pelvic floor muscle exercises, but evidence supporting the benefits of such exercises is scarce. We aimed to establish the effectiveness of one-to-one individualised pelvic floor muscle training for reducing prolapse symptoms. Methods We did a parallel-group, multicentre, randomised controlled trial at 23 centres in the UK, one in New Zealand, and one in Australia, between June 22, 2007, and April 9, 2010. Female outpatients with newly-diagnosed, symptomatic stage I, II, or III prolapse were randomly assigned (1:1), by remote computer allocation with minimsation, to receive an individualised programme of pelvic floor muscle training or a prolapse lifestyle advice leaflet and no muscle training (control group). Outcome assessors, and investigators who were gynaecologists at trial sites, were masked to group allocation; the statistician was masked until after data analysis. Our primary endpoint was participants' self-report of prolapse symptoms at 12 months. Analysis was by intention-to-treat analysis. This trial is registered, number ISRCTN35911035. Findings 447 eligible patients were randomised to the intervention group (n=225) or the control group (n=222). 377 (84%) participants completed follow-up for questionnaires at 6 months and 295 (66%) for questionnaires at 12 months. Women in the intervention group reported fewer prolapse symptoms (ie, a significantly greater reduction in the pelvic organ prolapse symptom score [POP-SS]) at 12 months than those in the control group (mean reduction in POP-SS from baseline 3 • 77 [SD 5 • 62] vs 2 • 09 [5 • 39]; adjusted difference 1 • 52, 95% CI 0 • 46-2 • 59; p=0 • 0053). Findings were robust to missing data. Eight adverse events (six vaginal symptoms, one case of back pain, and one case of abdominal pain) and one unexpected serious adverse event, all in women from the intervention group, were regarded as unrelated to the intervention or to participation in the study. Interpretation One-to-one pelvic floor muscle training for prolapse is effective for improvement of prolapse symptoms. Long-term benefits should be investigated, as should the effects in specific subgroups. Funding Chief Scientist Office of the Scottish Government Health and Social Care Directorates, New Zealand Lottery Board, and National Health and Medical Research Council (Australia). [ABSTRACT FROM AUTHOR]

The article offers information regarding the effects of psychosocial stress on employee health. It mentions that job strain is a major risk factor for coronary heart disease. It presents a cohort analysis of men and women without coronary heart disease. It states that prevention of workplace stress might decrease disease incidence. Also investigated are the role of psychological factors, such as personality type, cognition, and psychological stress, in the cause of coronary heart disease.

The article discusses the adoption of the 2030 Agenda for Sustainable Development, a blueprint which is applicable to every nation and which aims for equality among nations in the world. Topics discussed include an overview of the blueprint, the engagement of future generations through sustainability, the efforts the maintenance of peace and the promotion of human rights, and the issues associated with adolescent health and wellbeing.

The article discusses research on the use of antifungal agent isavuconazole in treating invasive mould infection. Topics discussed include results of the study, an overview of invasive mould infection, the use of isavuconazole in replacement of voriconazole as standard treatment for the infection, and the recommendations on patient outcome monitoring.

The article presents the results of the Liraglutide Efficacy and Action in Non-alcoholic steatohepatitis (LEAN) study on overweight patients and shows histological evidence of non-alcoholic steatohepatitis. It states that liraglutide, a human glucagon-like peptide-1 (GLP-1) analogue can reduce the reduce the glycosylated haemoglobin (HbA) concentrations by about 1 percent. It mentions that liraglutide treatment results to the improvement of serum concentration of glucose.

The author discusses the study of infant formulation in Bangladesh, Brazil, Indonesia, Nigeria, the Philippines, and Great Britain. The author states the importance of breastfeeding, the aggressive and active promotion of breastmilk substitutes (BMS), and international leadership to stimulate strategic action such as role of the governments for the implementation of international breastfeeding and increase the use of BMS.

The article discusses a study which investigated the intervention effects on diabetes incidence, weight change and cardiovascular risk factors and their treatment during a 10-year follow-up since the Diabetes Prevention Program (DPP) randomisation. All three groups that participated in the study were offered group-implemented lifestyle intervention and metformin treatment. The study showed that the original lifestyle group lost, then partly regained weight during the 10-year follow-up. In the intensive lifestyle intervention group, diabetes incidence rates during the DPP were 4.8 cases per 100 person-years.

The article presents research investigating the association of body-mass index (BMI) with overall and cause-specific mortality by analyzing the data from several studies. The methods used in the collaborative analysis of baseline BMI versus mortality in 57 prospective studies involving nearly 900,000 participants in described. Results suggest that BMI is a strong predictor of overall mortality both above and below the optimum range of 25.5 to 25 kg/m², while progressive excess mortality above this range is due mostly to vascular disease.

The article discusses a study that compared the European Action on Secondary and Primary Prevention by Intervention to Reduce Events (EUROASPIRE) I, II, and III surveys, conducted in eight European countries to evaluate cardiovascular disease prevention. The third survey investigated whether recommendations of the Joint European Societies are being followed. Smoking, obesity, raised blood pressure, and raised cholesterol were examined. Researchers found a compelling need for more effective lifestyle management of patients with coronary heart disease. They found that blood pressure remained unchanged and that almost half of all patients were above the recommended target for lipids. They express the need to invest in prevention.

The first in a series of papers on health in the occupied Palestinian territory is presented. The demographic characteristics, health status, and health services of the Palestinian population living in Israeli-occupied Palestinian territory are described. The public-health and health-service response to health problems is examined. Health status is described using subjective measures in addition to conventional indicators. The relevance of the indicators and analytical framework for the assessment of health in populations living in continuous war conditions is also discussed. INSET: Panel: A brief history of the occupied Palestinian territory.

The article reviews the mechanisms by which obstructive sleep apnoea (OSA) may contribute to the pathogenesis of cardiovascular disease. It also assesses epidemiological evidence for the link between the conditions and reviews cardiovascular effects of treating OSA with treatments such as continuous positive airway pressure (CPAP). Obstructive sleep apnoea is described as a disorder in which repetitive apnoeas create cycles of hypoxia, exaggerated negative intrathoracic pressure, and arousals. OSA has been shown to be associated with hypertension, arrhythmias, coronary artery disease, heart failure, and stroke. The association of OSA to habitual snoring is also mentioned. The pathophysiology and epidemiology that includes prevalence and risk factors is discussed.

This article discusses a subgroup analysis of the relationship between heart rate and complications in the rehabilitation of patients with heart disease. Results from a study called BEAUTIFUL, which stands for morBidity-mortality EvAlUation of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction, are analysed. This study monitored the effects of ivabradine on patients taking β blockers to prevent complications resulting from coronary heart disease, and in the process it disaggregated data on heart rate and health from related issues of exercise and physical fitness. Evidence of a correlation between heart rate and risk of cardiac event is presented.

This article discusses a study of the pharmaceutical control of heart rate as a method for preventing complications in patients with coronary artery disease and left-ventricular systolic dysfunction. The study was given the acronym BEAUTIFUL, which stands for morBidity-mortality EvAlUation of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction. This study monitored the effects of ivabradine on patients taking β blockers on patients with elevated heart rates and the above mentioned cardiac issues.

This article presents the results of a phase two clinical trial of a cystic fibrosis medication that eliminates nonsense mutations in the messenger RNA (mRNA) of the cystic fibrosis transmembrane conductance regulator (CFTR). This medication, called PTC124, works by causing ribosomes to selectively read through stop codons created by nonsense mutations in the course of mRNA translation. To measure the effectiveness of this medication, researchers observed mean total chloride transport in the nasal potential difference (PD) measurement of cystic fibrosis patients. The drug was judged preliminarily effective.

This article discusses the genetic aspects of long and short QT syndromes, which are irregularities in depolarization and repolarization of the ventricles leading to tachyrhythmia and torsades de pointes. Mutations in the proteins responsible for the formation of ionized sodium (Na+) and potassium (K+) channels are presented as a cause of long QT syndrome (LQTS). The series of genetic mutations that can cause short QT syndrome (SQTS), LQTS and other issues including Andersen-Tawil syndrome, Brugada syndrome, and catecholaminic polymorphic ventricular tachycardia is addressed. The relationship between these different diseases and the electrocardiographic readings that they cause is explored. Treatment options are also noted.

The article presents a study assessing the prevalence and mortality risks associated with all stages of chronic kidney disease and quantifiable mortality in Taiwan. The setting and design of the cohort study involving over 400,000 individuals over the age of 20 that were screened since 1994 are outlined. Calculations of mortality attributed to chronic kidney disease from 14, 436 identified deaths were used to determine national prevalence of the disease in Taiwan. Researchers found a high prevalence of chronic kidney disease mortality was associated with low socioeconomic status. Scientists recommend making the disease a public-health priority and suggest a promotion of urine protein testing and glomerular filtration rate testing to prevent premature deaths from the condition.

The article presents a review of available evidence concerning the use of controlled hypothermia and fever control for the prevention of neurological injuries in patients who have suffered traumatic brain injury, stroke, hepatic encephalopathy and myocardial infarction. The review also seeks to provide a guide for the effective management of the side effects associated with induced hypothermia. Particular attention is paid to the rate of rewarming as an important factor in establishing successful implementation of hypothermia to treat neurological injuries.

The article presents an over view of the prevalence, pathogenesis and causes of chronic cough in adults, which is a cough that has lasted for at least eight weeks. A discussion of the function of coughing, which is a reflex action of the respiratory tract which is used by humans to clear their upper airways, is presented. Serious pulmonary and extrapulmonary pathological conditions which cough can be the first indication of and conditions that care often associated with chronic cough are discussed. An examination of research which has been conducted on cough is offered.

The article presents a cluster randomized trial to determine if earlier age-based preventive targeting of childhood nutrition programs could reduce childhood malnutrition in developing countries. Most such programs have used a benchmark of five years or younger, and the trial attempts to determine if a lower benchmark would be more effective, and if preventive targeting of nursing mothers is more effective than remedial nutrition. Two childhood nutrition programs in Haiti were examined in the trial. The results showed that preventive targeting was more effective in reducing cases of child malnutrition.

The article presents a meta-analysis and review of studies on the link between excess weight as expressed by the body-mass index and the incidence of cancer. Some 141 articles containing over 280,000 cases were examined. Using the benchmark of a 5 kilogram/meter increase in body mass, strong links between cancer and excess weight were found in men for esophagal, thyroid, and colon cancers, and in women with gallbladder and renal cancers.

In this Review, we look at the relation between bereavement and physical and mental health. Although grief is not a disease and most people adjust without professional psychological intervention, bereavement is associated with excess risk of mortality, particularly in the early weeks and months after loss. It is related to decrements in physical health, indicated by presence of symptoms and illnesses, and use of medical services. Furthermore, bereaved individuals report diverse psychological reactions. For a few people, mental disorders or complications in the grieving process ensue. We summarise research on risk factors that increase vulnerability of some bereaved individuals. Diverse factors (circumstances of death, intrapersonal and interpersonal variables, ways of coping) are likely to co-determine excesses in ill-health. We also assess the effectiveness of psychological intervention programmes. Intervention should be targeted at high-risk people and those with complicated grief or bereavement-related depression and stress disorders. [ABSTRACT FROM AUTHOR]

This article presents a seminar on stillbirth in Great Britain which has been increasing. The authors believe the increase may be due to older maternal ages, obesity and diabetes. Many stillbirths are the result of placental dysfunction which in some women is evident early on and in others is not. There is no effective screening method to identify high-risk women or to then offer them successful treatment. The definition of stillbirth is given along with classifications. The largest number of stillbirth are still unexplained. Rates and causes of stillbirth are compared between developed and developing countries.

This article presents a seminar on sudden infant death syndrome (SIDS). While the rates of SIDS are declining, it is still the leading cause of death of very young infants age 1 month to 1 year in developed countries. Factors that are blamed for SIDS include the sleeping position of the baby, second hand smoke exposure, bedding that is too soft and overheating. Pacifiers and one child per bed appear to reduce the risk of sudden infant death. The exact cause of SIDS is still unknown though it is suspected that immature cardiorespiratory control and failure of arousal from sleep are causes in addition to possible genetic factors.

This article presents the results of a study looking into the risk of chronic obstructive pulmonary disease (COPD) in those exposed to second hand smoke in China. COPD is a leading cause of death in China where a large number of the population is exposed to second hand smoke. The study discovered that exposure to passive smoking is associated with an increased prevalence of COPD and respiratory symptoms. If the association is causal, the study authors' estimate that 1.9 million deaths from COPD among nonsmokers could be attributed to passive smoking in China.

The article discusses a study analyzing how exposure to substances in the workplace contributes to new-onset asthma. Participants without history of respiratory illness who had participated in the European Community Health Study were tested for asthma by methacholine challenge test. Log-binomial models were used to calculate risks for onset asthma by job exposure. The study indicated that asthma risks increased with occupational exposure to certain substances. Asthma risk was increased in nursing and for participants who reported inhalation events such as with fire, chemical spills, and the mixing of cleaning materials. Bronchial hyper-activity was the most common form of asthma reported.

The authors discuss the effects of hypertension on the eye. They discuss hypertensive retinopathy, which is predictive for incident stroke, congestive heart failure and cardiovascular mortality. Hypertension is also a risk factor for the development of retinal vascular diseases, including retinal vein and artery occlusion. The authors mention that high blood pressure increases the risk of developing diabetic retinopathy. Blood pressure control has been proven to reduce vision loss that is linked to diabetic retinopathy in clinical trails. Hypertension has also been implicated in the cause of glaucoma and age-related macular degeneration.